Planning preclinical confirmatory multicenter trials to strengthen translation from basic to clinical research – a multi-stakeholder workshop report

Clinical translation from bench to bedside often remains challenging even despite promising preclinical evidence. Among many drivers like biological complexity or poorly understood disease pathology, preclinical evidence often lacks desired robustness. Reasons include low sample sizes, selective reporting, publication bias, and consequently inflated effect sizes. In this context, there is growing consensus that confirmatory multicenter studies -by weeding out false positives- represent an important step in strengthening and generating preclinical evidence before moving on to clinical research. However, there is little guidance on what such a preclinical confirmatory study entails and when it should be conducted in the research trajectory. To close this gap, we organized a workshop to bring together statisticians, clinicians, preclinical scientists, and meta-researcher to discuss and develop recommendations that are solution-oriented and feasible for practitioners. Herein, we summarize and review current approaches and outline strategies that provide decision-critical guidance on when to start and subsequently how to plan a confirmatory study. We define a set of minimum criteria and strategies to strengthen validity before engaging in a confirmatory preclinical trial, including sample size considerations that take the inherent uncertainty of initial (exploratory) studies into account. Beyond this specific guidance, we highlight knowledge gaps that require further research and discuss the role of confirmatory studies in translational biomedical research. In conclusion, this workshop report highlights the need for close interaction and open and honest debate between statisticians, preclinical scientists, meta-researchers (that conduct research on research), and clinicians already at an early stage of a given preclinical research trajectory

Real-Time Fluorescence Loop Mediated Isothermal Amplification for the Diagnosis of Malaria

BACKGROUND: Molecular diagnostic methods can complement existing tools to improve the diagnosis of malaria. However, they require good laboratory infrastructure thereby restricting their use to reference laboratories and research studies. Therefore, adopting molecular tools for routine use in malaria endemic countries will require simpler molecular platforms. The recently developed loop-mediated isothermal amplification (LAMP) method is relatively simple and can be improved for better use in endemic countries. In this study, we attempted to improve this method for malaria diagnosis by using a simple and portable device capable of performing both the amplification and detection (by fluorescence) of LAMP in one platform. We refer to this as the RealAmp method. METHODOLOGY AND SIGNIFICANT FINDINGS: Published genus-specific primers were used to test the utility of this method. DNA derived from different species of malaria parasites was used for the initial characterization. Clinical samples of P. falciparum were used to determine the sensitivity and specificity of this system compared to microscopy and a nested PCR method. Additionally, directly boiled parasite preparations were compared with a conventional DNA isolation method. The RealAmp method was found to be simple and allowed real-time detection of DNA amplification. The time to amplification varied but was generally less than 60 minutes. All human-infecting Plasmodium species were detected. The sensitivity and specificity of RealAmp in detecting P. falciparum was 96.7% and 91.7% respectively, compared to microscopy and 98.9% and 100% respectively, compared to a standard nested PCR method. In addition, this method consistently detected P. falciparum from directly boiled blood samples. CONCLUSION: This RealAmp method has great potential as a field usable molecular tool for diagnosis of malaria. This tool can provide an alternative to conventional PCR based diagnostic methods for field use in clinical and operational programs

Estimating loss of Brucella abortus antibodies from age-specific serological data in elk

Serological data are one of the primary sources of information for disease monitoring in wildlife. However, the duration of the seropositive status of exposed individuals is almost always unknown for many free-ranging host species. Directly estimating rates of antibody loss typically requires difficult longitudinal sampling of individuals following seroconversion. Instead, we propose a Bayesian statistical approach linking age and serological data to a mechanistic epidemiological model to infer brucellosis infection, the probability of antibody loss, and recovery rates of elk (Cervus canadensis) in the Greater Yellowstone Ecosystem. We found that seroprevalence declined above the age of ten, with no evidence of disease-induced mortality. The probability of antibody loss was estimated to be 0.70 per year after a five-year period of seropositivity and the basic reproduction number for brucellosis to 2.13. Our results suggest that individuals are unlikely to become re-infected because models with this mechanism were unable to reproduce a significant decline in seroprevalence in older individuals. This study highlights the possible implications of antibody loss, which could bias our estimation of critical epidemiological parameters for wildlife disease management based on serological data

Cosmic Rays and the Search for a Lorentz Invariance Violation

This is an introductory review about the on-going search for a signal of Lorentz Invariance Violation (LIV) in cosmic rays. We first summarise basic aspects of cosmic rays, focusing on rays of ultra high energy (UHECRs). We discuss the Greisen-Zatsepin-Kuz'min (GZK) energy cutoff for cosmic protons, which is predicted due to photopion production in the Cosmic Microwave Background (CMB). This is a process of modest energy in the proton rest frame. It can be investigated to a high precision in the laboratory, if Lorentz transformations apply even at factors $\gamma \sim O(10^{11})$. For heavier nuclei the energy attenuation is even faster due to photo-disintegration, again if this process is Lorentz invariant. Hence the viability of Lorentz symmetry up to tremendous gamma-factors - far beyond accelerator tests - is a central issue. Next we comment on conceptual aspects of Lorentz Invariance and the possibility of its spontaneous breaking. This could lead to slightly particle dependent ``Maximal Attainable Velocities''. We discuss their effect in decays, Cerenkov radiation, the GZK cutoff and neutrino oscillation in cosmic rays. We also review the search for LIV in cosmic gamma-rays. For multi TeV gamma-rays we possibly encounter another puzzle related to the transparency of the CMB, similar to the GZK cutoff. The photons emitted in a Gamma Ray Burst occur at lower energies, but their very long path provides access to information not far from the Planck scale. No LIV has been observed so far. However, even extremely tiny LIV effects could change the predictions for cosmic ray physics drastically. An Appendix is devoted to the recent hypothesis by the Pierre Auger Collaboration, which identifies nearby Active Galactic Nuclei - or objects next to them - as probable UHECR sources.Comment: 81 pages, 15 figures, some points extended and improved, references adde

Compound sums approximations and reliability applications

Available from INIST (FR), Document Supply Service, under shelf-number : 22522, issue : a.2001 n.4 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueSIGLEFRFranc

Wavelet estimation of a multifractal function

SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : 22522, issue : a.2003 n.4 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Bins and balls : large deviations of the empirical occupancy process

SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : 22522, issue : a.2000 n.12 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Large deviations for random power moment problem

SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : 22522, issue : a.2003 n.3 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc